drugs

GMP’s for Early Stage Development of New Drug substances and products

The question of how Good Manufacturing Practice (GMP) guidelines should be applied during early stages of development continues to be discussed across the industry and is now the subject of a new initiative by the International Consortium on Innovation and Quality in Pharmaceutical Development (IQ Consortium)—an association of pharmaceutical and biotechnology companies aiming to advance innovation and quality in the development of pharmaceuticals. They have assembled a multidisciplinary team (GMPs in Early Development Working Group) to explore and define common industry approaches and to come up with suggestions for a harmonized approach. Their initial thoughts and conclusions are summarized in Pharm. Technol. 2012, 36 (6), 54–58.

From an industry perspective, it is common to consider the “early” phase of development as covering phases 1 and 2a clinical studies. During this phase, there is a high rate of product attrition and a high probability for intentionally introducing change into synthetic processes, dosage forms, analytical methods, and specifications. The quality system implemented during this early phase should take into account that these changes and adjustments are intrinsic to the work being performed prior to the determination of the final process and validation of the analytical methods during later stages of development.

FDA guidance is already available on GMP requirements for phase 1 materials. (See Org. Process. Res. Dev. 2008, 12, 817.) Because many aspects of phase 2a clinical studies are similar in their scope and expectations, the working group feels there is an opportunity to extend this guidance across all early phase studies. Because products and processes are less well understood in the early phases of development, activities should focus on accumulating the appropriate knowledge to adequately ensure patient safety. Focusing on this area should ensure that beneficial therapies reach the clinic in an optimum time scale with minimal safety concerns.

A follow-up article ( Pharm. Technol. 2012, 36 (7), 76−84) describes the working group’s approach to the subject of Analytical Method Validation. Their assessment has uncovered the need to differentiate the terms “validation” and “qualification”. Method qualification is based on the type, intended purpose, and scientific understanding of the type of method in use. Although not used for GMP release of clinical materials, qualified methods are reliable experimental methods that may be used for characterization work such as reference standards and the scientific prediction of shelf life. For example, in early development it would be sufficient for methods used for in-process testing to be qualified, whereas those methods used for release testing and for stability determination would be more fully validated.

In early development, a major purpose of analytical methods is to determine the potency of APIs and drug products to ensure that the correct dose is delivered in the clinic. Methods should also indicate stability, identify impurities and degradants, and allow characterization of key attributes. In the later stages, when processes are locked and need to be transferred to worldwide manufacturing facilities, methods need to be cost-effective, operationally viable, and suitably robust such that the methods will perform consistently. irrespective of where they are executed.

The authors advocate that the same amount of rigorous and extensive method-validation experiments, as described in ICH Q2, “Analytical Validation”, is not needed for methods used to support early stage drug development. For example, parameters involving interlaboratory studies (i.e., intermediate precision, reproducibility, and robustness) are not typically performed during early phase development, being replaced by appropriate method-transfer assessments and verified by system suitability requirements. Because of changes in synthetic routes and formulations, the impurities and degradation products formed may change during development.

Accordingly, related substances are often determined using area percentage by assuming that the relative response factors are similar to that of the API. As a result, extensive studies to demonstrate mass balance are typically not conducted during early development.

Detailed recommendations are provided for each aspect of method validation (specificity, accuracy, precision, limit of detection, limit of quantitation, linearity, range, robustness) according to the nature of the test (identification, assay, impurity, physical tests) for both early- and late phase development. These recommendations are also neatly summarized in a matrix form.

Due to the high attrition rate in early development, the focus should be on consistent specifications that ensure patient safety, supported by preclinical and early clinical safety studies. On the basis of the cumulative industry experience of the IQ working group members, the authors of this paper propose standardized early phase specification tests and acceptance criteria for both drug substance and drug product. In addition to release and stability tests, consideration is given to internal tests and acceptance criteria that are not normally part of formal specifications, but which may be performed to collect information for product and process understanding or to provide greater control.

The drug substance used in preclinical animal studies (tox batch) is fundamental in defining the specifications for an early phase clinical drug substance (DS). Here, internal targets rather than formal specifications are routinely used while gathering knowledge about impurities and processing capabilities. At this stage the emphasis should be on ensuring the correct DS is administered, determining the correct potency value, and quantitating impurities for toxicology purposes. For DS intended for clinical studies, additional testing and controls may be required; the testing may be similar to that for the tox batch, but now with established acceptance criteria. For these stages the authors propose a standardized set of DS specifications, as follows.

Description

range of colour

identification

conforms to a reference spectrum

counterion

report results

assay

97–103% on a dry basis

impurities

NMT 3.0% total, NMT 1.0% each

unidentified

NMT 0.3%

unqualified

NMT 0.15%

mutagenic

follow EMA guidelines (pending ICH M7 guidance)

inorganic

follow EMA guidelines (pending ICH Q3D guidance)

residual solvents

use ICH Q3C limits or other justified limits for solvents used in final synthetic step

water content

report results

solid form

report results

particle size

report results

residue on ignition

NMT 1.0%

These may be altered in line with any specific knowledge of the compound in question. For example, if the DS is a hydrate or is known to be hygroscopic or sensitive to water, a specified water content may be appropriate. Of particular note is the use of impurity thresholds which are 3 times higher than those defined in ICH Q3 guidelines. Q3 was never intended to apply to clinical drugs, and higher thresholds can be justified by the limited exposure that patients experience during these early stages. Mutagenic impurities are the exception here, since in this area the existing official guidance does cover clinical drugs.

Often non-GMP DS batches are manufactured first and placed on stability to support a variety of product development activities.In many cases these batches will be representative of subsequent GMP batches from a stability perspective and can be used to establish an initial retest period for the DS and support a clinical submission. In early development, it is common for the manufacturing process to be improved; therefore, as the DS process evolves, an evaluation is needed to determine whether the initial batch placed on stability is still representative of the improved process. The authors advocate a science- and risk-based approach for deciding whether stability studies on new process batches are warranted.

The first step is to determine which DS attributes have an effect on stability. This step can be completed through paper-based risk assessments, prior knowledge, or through a head-to-head short-term stability challenge. If the revised process impacts one or more of these stability-related quality attributes, the new batch should be placed on stability—otherwise not. Typical changes encountered at this stage include changes in synthetic pathway, batch scale, manufacturing equipment or site, reagents, source materials, solvents used, and crystallization steps.

In most cases, these changes will not result in changes in DS stability. Changes to the impurity profile are unlikely to affect stability, since most organically related impurities will be inert. On the other hand, catalytic metals, acidic or basic inorganic impurities, or significant amounts of residual water or solvents may affect stability; thus, changes to these attributes would typically require the new batch to be placed in the stability program. Similarly, any changes to polymorphic form, particle size, or counterion would warrant extra testing. Packaging changes of the bulk material to a less protective package may require stability data to support the change.

Three approaches to stability data collection are commonly used. One is that an early, representative DS batch is placed under real-time and accelerated conditions (e.g., 25 °C/60% RH and 40 °C/75% RH), and stability results for a few time points (e.g., 1–6 months) are generated to support an initial retest period (e.g., 12 months or more). A second approach is to use high stress conditions such as a high temperature and high humidity with a short time. A third approach is the use of stress studies at several conditions coupled with modelling. The retest period derived from these types of accelerated or stress studies can be later verified by placing the first clinical batch into real-time stability studies under ICH accelerated and long-term conditions. Future extensions of the retest/use period can be based on real-time data.

The Procedure for Manufacturing Drugs in Mie Prefecture, Japan.

The following details the necessary procedure for the commencement of manufacture (or importing) of drugs in Mie Prefecture, Japan. Note: The procedures described below are applicable in Mie Prefecture, Japan, as of April 2002. Due to future amendments and the disparities of laws in different prefectures, it is necessary to be informed as to the correct application procedures directly by the relevant prefecture.

1. For Manufacture (or Importing) of Drugs

Approval for the manufacture (importing) of each item, and a manufacturing (importing) license are required for the manufacture (or importing) of drugs.

Drug Manufacture

Approval

The quality, effectiveness and safety of the drug under application must pass the examination. However, drugs listed on the Pharmacopoeia of Japan do not require approval.

License

The structural conditions (building and facilities) and human resource requirements (e.g. Administrators) of the drug manufacturing facilities must pass the examination to acquire a business license.

2. Standard Period for the Administrative Process

There is a standard period for the administrative process of the approval and licensing examinations. Unless there are irregularities in the application or supplied data, the examinations are generally completed within the time specified.

(Example)

*Approval

Ethical Drugs

(new drugs)

1 year

(branded generic drugs)

1 year

(modification)

1 year

Non-prescription drugs

10 months

IVD (in vitro diagnostic)

6 months (approval for modification of storage conditions and period of effectiveness: 3 months)

*Mie Prefectural License (for manufacture or importing)

Drugs, quasi-drugs, cosmetics, or new medical devices

56 days

Note: (1) The above periods for approval and licensing are applicable only in Mie Prefecture. Be aware that the standard periods for the administration process may differ in other prefectures. Further, the above period may be extended where a replacement of the application documents is required. (2) Please feel free to contact us if you have any further questions.

3. Drug Approval Inspection

Apart from those drugs which do not require approval, most drugs are approved by the Minister of Health, Labor and Welfare, and some are approved by the Governor. However, approval and receipt of applications based on both national and prefectural standards will occur at the prefectural government. The drug approval process is detailed below. Quasi-drugs, and medical devices are approved under the same process as drugs. As for cosmetics, those which contain ingredients that are not displayed, require approval.

4. License for Drug Manufacture (or Importing)

Below is a flowchart illustrating the license application process in Mie Prefecture. Applications are accepted by the Mie Prefectural Government.

At present, provided that there are no problems found at the site inspection, licensing will take 2 weeks. If you require licensing within 2 weeks due to your production schedule, with advance notice, we may give you special consideration and shorten the duration of the licensing process. The license is valid for 5 years, and must be renewed after 5 years. In addition, the application process for the business license for manufacturers (and importers) of quasi-drugs, cosmetics, and medical devices is the same as for a drug manufacturer (or importer).

With an improved clinical trial infrastructure now a high priority, Japan offers an advantageous development environment for pharmaceutical, biotechnology, and medical device companies. To address a decade-long downward trend in trial applications and a lag in the availability of drugs within the country as compared to other developed nations, Japan’s Ministry of Health, Labor and Welfare (MHLW) has ushered in significant changes in recent years. These include bold steps to create a more welcoming and efficient approach to trials while maintaining global standards such as those of the International Conference on Harmonization/ Good Clinical Practice (ICH-GCP).

Revisions to the Pharmaceutical Affairs Law (PAL) of 2005 indicate that indeed the Japanese regulatory review process is in a new era. While the process continues to pose challenges, significant development opportunities now exist for organizations that successfully navigate this transitional terrain.

This article presents an overview of the Japanese population for clinical studies as well as the regulatory environment, with emphasis on how regulations differ from ICH-GCP standards.

Market Characteristics

The 127 million people of Japan make up a population whose total has remained unchanged for the last 20 years due to a declining birthrate. The population is aging and boasts the world’s longest average lifespan at 79.19 years for men and 85.99 years for women, according to the CIA World Factbook, 2009.

Japan is the second largest market worldwide in terms of pharmaceutical sales, behind the US and just ahead of China. According to IMS Health, sales grew 7.6% in 2009 over 2008. This high rate of pharmaceutical consumption is an irony given the fact that many top-selling products globally have not even been made available in Japan due to the lengthy and expensive trial and approval process.

National Healthcare Provision

Healthcare services in Japan are provided by national and local governments offering relative equality of access, with fees set by committee. People without insurance from employers can participate in a national program administered by the local government. All elderly are also covered by a government program. Patients may select physicians and facilities of their choice.

A Fresh, Welcoming Environment

With recent amendments to PAL, drug and device developers can now plan and conduct clinical trials in Japan under Clinical Trial Notifications (CTNs), which are reviewed in just 30 days, a turnaround time comparable to that achieved in the US. A grant program subsidized by MHLW is designed to accelerate the development of high-priority drugs and medical devices recommended by the member societies of the Japanese Association of Medical Sciences (JAMS) that are:

Widely used as standard treatment in the US or Europe but not yet approved in Japan

Already marketed in Japan and commonly used for off-label indications1

Interest in revitalizing the clinical trials process in Japan is increasingly obvious through improved infrastructure, IT investments, and education of physicians and patients on the need for reform. The Japanese market offers dedicated research teams within national and university hospitals across a variety of therapy areas. Networks such as the National Hospital Organization facilitate reaching into both large- and medium-sized cities with multiinstitutional studies and clinical trials. Such an environment offers direct access to healthcare professionals, including a solid network of primary care physicians.

The Japanese market also can make accessible large groups of aging, recurrent patients in specific therapy areas. And, although a variety of dialects are spoken, the Japanese communicate via one standard language, making communicating with patients and investigators easier.

Japanese investigators participate in international conferences and are ICH-GCP and Japan GCP compliant. As the government wants to maintain and encourage further research within the country, both on-site and centralized Institutional Review Boards (IRBs) convene regularly (as often as once a month) to keep the clinical study process moving. Centralized IRBs that are managed by Site Management Organizations (SMOs) are especially flexible in this regard.

Another advantage is that smaller communities within hospital regions develop strong patient/research links, so patients tend to be compliant, and sites increasingly deliver the predicted patient numbers.

Remaining Hurdles Require In-Country Expertise

Although Japan provides high-density populations in urban areas, patients can be difficult to recruit because of their easy access to healthcare coverage. The lack of an incentive to participate, coupled with little awareness of the need for trials, continues to be problematic and adds to the trial timeline.

What is more, the cost of conducting clinical trials in Japan remains higher than in the West because of the need to use SMOs, which add labor costs. There is no specialized research hospital in Japan, so SMOs, having access to a pool of patients, are essential.

Trials also tend to take longer for a range of reasons – from the lack of patient incentives and lower physician incentives to the still maturing infrastructure.

Due to the complexities of conducting research in Japan, corporate sponsors should ensure that they have ready access to in-country experts.

The Regulatory Landscape

Recent changes to the regulatory system for pharmaceuticals and medical devices have enabled Japan to align its safety measures more closely with those of other developed nations. Since its establishment in 2004, the Pharmaceuticals and Medical Devices Agency (PMDA) has provided comprehensive risk management from pre-clinical research to approval through three functions: review (risk reduction), safety (continuous risk mitigation), and relief (services for adverse health effects).

Improving the infrastructure for clinical trials has been a primary focus in Japan. The Center for Clinical Trials of the JMA (JMACCT) was also established in 2004 to promptly provide the public with medically necessary or new pharmaceutical products and medical devices, organize multiple medical institutions into a network, and conduct model clinical trials.

The current regulatory environment in Japan encompasses:

Procedures for Drug Approval Applications (NDAs)

The application is made after completion of nonclinical and clinical trials

Required GCP, GLP, and GMP surveys should be applied for immediately after the NDA submission

The manufacturer and/or distributor must be authorized and, if a manufacturing plant is overseas, the appropriate accreditation must be obtained

Information must include the origin or background of discovery, characteristics and efficacy, records of consultation with PMDA, a list of drugs of the same type/indication, conditions of use in other countries, and package inserts

NDA Review Process

PMDA frequently performs a team review with experts in quality, nonclinical, and clinical trials, biostatistics, and other fields.

Notification of Clinical Trial Plan

The Minister in charge of Clinical Trial Protocols must be notified in advance of trials for drugs with new active ingredients, new routes of administration, new combination drugs, new indications, new dosages, and biologics.

Scope of Reporting

When performing a clinical trial, the following information must be reported:

Unexpected death or cases of adverse experiences potentially leading to death

Measures taken in foreign countries to prevent the occurrence or spread of risk to public health and hygiene (including discontinuation of manufacturing, import, or marketing or withdrawal or disposal of an item with ingredients equivalent to those of test products; also including revision of the precautions, accompanied by a letter to the distributing doctor)

Research reports indicating the possibility of the drug causing cancer or any other serious disease due to adverse reactions or showing a lack of anticipated efficacy or clinical benefit

While the precise wording differs, the reporting requirements in Japan reflect the spirit of those in Western markets. The EU, for example, requires that sponsors report untoward medical occurrences from any dose that result in death, are life threatening, require or prolong hospitalization, lead to persistent or significant disability, or a congenital anomaly or birth defect.

Differences Between Japan’s GCP and ICH-GCP

Japanese regulatory authorities are particularly eager to avoid any misconduct related to clinical trials, such as past deficiencies in case report forms (CRFs), informed consent, institutional review board practices, and protocol deviations. Transparency is a primary goal for the revised process.

Japan’s GCP places greater responsibility on the institute and its head such that:

The contract is between the sponsor and the institute, not between the sponsor and the investigator

Items covered in the contract must be defined

Each institute must have an IRB

The sponsor must prepare a policy for compensating trial participants for any injuries during the trial prior to submitting documents to the IRB. This policy must be included while obtaining informed consent. In the case of injury, “the subject should be adequately compensated regardless of whether or not the injury is due to negligence. The subject is not burdened with providing a causal relationship.”

A sponsor that does not have an address in Japan must select an In-Country Caretaker (ICC). A CRO in Japan can act as the ICC on behalf of the sponsor. (See sidebar on ICC Responsibilities.)

Product labels must be in Japanese.

Safety information must be reported periodically (such as every six months) after submission of the initial Clinical Trial Notification (CTN) and within two months after the study is completed.

According to the ICH guidelines, (sections, 5.16.1/2 and 5.17) sponsors are to promptly notify all concerned investigators, institutions, and authorities of findings that could adversely affect subjects’ safety or the course of the trial. Suspected, unexpected serious adverse reactions require expedited reporting, while all other safety information can be included in an annual safety report.

While many of the provisions are similar, any differences between Japan’s GCP and ICH-GCP must be understood and acted upon. The sponsor should be certain that a regulatory expert is engaged and available for consultation during the clinical trial process.

Conclusion

In the realm of clinical trials, Japan may still be a “developing” country, but is certainly one focused on revitalization and global harmonization. Increased demand and resources for pharmaceutical and medical device research have spurred a new era of reform with the budgets and resources required. Not all the challenges have been addressed, but a more stable and effective infrastructure, network, and standards are now in place. In planning for global studies, sponsors can now be assured that Japan is ready to participate from the outset and is governed by regulations that are tracked closely with the International Conference on Harmonization standards.

References

ICC Responsibilities

The In-Country Caretaker (ICC) is responsible for the progress of clinical trials and must be the primary contact for any regulatory interaction on behalf of the sponsor company. The ICC oversees:

All clinical development work on behalf of the sponsor

Submission of a Clinical Trial Notification (CTN) to the PMDA

Replies to questions raised by the PMDA

Supply of the investigational drug, including customs clearance, requests made to the drug depot or the contract manufacturing organization (CMO), and the checking of manufacturing records and QC tests

Monitoring of the clinical trial and preparation of the Clinical Study Report (CSR)

Collection and reporting of information on adverse reactions, including from overseas

Translation of documents and data (English to Japanese / Japanese to English)

methodology provides a risk-based approach to residual solvent
analysis that considers a patient’s exposure to a solvent residue
in the drug product. Solvents have been classified based on their
potential health risks into three main classes:
1. Class 1: Solvents should not be used because of the
unacceptable toxicities or deleterious environmental effects.
2. Class 2: Solvents should be limited because of inherent
toxicities.
3. Class 3: Solvents may be regarded as less toxic and of lower
risk to human health.
Testing is only required for those solvents used in the
manufacturing or purification process of drug substances, excipients
or products. This allows each company to determine which solvents
it uses in production and develop testing procedures that address
their specific needs. It is the responsibility of the drug manufacturer
to qualify the purity of all the components used in the manufacturing
of the drug product. This would pertain to items such as excipients,
of which some contain residual levels of Class 1 solvents by nature
of the manufacturing process and/or nature of the starting materials
(e.g. ethyl cellulose). The new 467 monograph provides an optional
method to determine when residual solvent testing is required for
Class 2 solvents. Each Class 2 solvent is assigned a permitted daily
exposure (PDE) limit, which is the pharmaceutically acceptable
intake level of a residual solvent.
The USP has provided a method for the identification, control,
and quantification of Class 1 and 2 residual solvents. The method
calls for a gas chromatographic (GC) analysis with flame ionization
detection (FID) and a headspace injection from either water or
organic diluent. The monograph has suggested two procedures:
Procedure A G43 (Zebron ZB-624) phase and Procedure B G16
(Zebron ZB-WAXplus) phase. Procedure A should be used first. If
a compound is determined to be above the specified concentration
limit, then Procedure B should be used to confirm its identity.
Since there are known co-elutions on both phases, the orthogonal
selectivity ensures that co-elutions on one phase will be resolved
on the other. Neither procedure is quantitative, so to determine
the concentration the monograph specifies Procedure C, which
utilizes whichever phase will give the fewest co-elutions. Class
3 solvents may be determined by 731-Loss on Drying unless the
level is expected to be >5000 ppm or 50 mg. If the loss on drying
is >0.5 %, then a water deterrmination should be performed using
921-Water Determination.
One of the most important considerations is that, once
implemented, the new method will pertain to all currently marketed
drug products as well as those in development and clinical trials8

United States Pharmacopoeia (USP):
In 1988, the United States Pharmacopoeia (USP) provided
control limits and testing criteria for seven organic volatile impurities
(OVIs) under official monograph 4678
. According to USP, testing
should be conducted only if a manufacturer has indicated the
possible presence of a solvent in a product. Testing may be avoided
when a manufacturer has assurance, based on the knowledge of
the manufacturing process and controlled handling, shipping, and
storage of the product, that no potential exists for specific solvents
to be present and that the product, if tested, will comply with the
accepted limit. Items shipped in airtight containers (such as those
used for food additives) can be considered not to have acquired
any solvents during transportation2
.
The compounds are chosen based on relative toxicity and only
applied to drug substances and some excipients8
. In addition, a
test for ethylene oxide is conducted if specified in the individual
monograph. Unless otherwise specified in the individual monograph,
the acceptable limit for ethylene oxide is 10 ppm. USP does not
address all other solvents mentioned in the ICH guideline2
.
In an effort to harmonize with the International Conference
for Harmonization (ICH), the USP has proposed the adoption of
a slightly modified version of ICH (Q3C) methodology, which has
been scheduled for implementation on July 1, 2007. The ICH Q3C

Organic Volatile Impurities
Of the solvents targeted in USP 26 General Chapter 467, only
methylene chloride may appear in bulk pharmaceutical products
manufactured by Pfizer at the Kalamazoo plant. For those products
where OVI testing is required, our material will meet the compendial
limits for methylene chloride and other solvents that may be added
to the target list in the future.
No OVI requirement exists in the USP 26 monograph
for Triamcinolone, but Triamcinolone from Pfizer meets the
requirements of USP 26 General Chapter 467.

Introduction
Residual solvents in pharmaceuticals, commonly known as
organic volatile impurities (OVIs), are chemicals that are either
used or produced during the manufacture of active pharmaceutical
ingredients (APIs), excipients and drug products1, 2
.
Organic solvents play an essential role in drug-substance and
excipient manufacture (e.g., reaction, separation and purification)
and in drug-product formulation (e.g., granulation and coating) 3
.
Some organic solvents are often used during the synthesis of active
pharmaceutical ingredients and excipients or during the preparation
of drug products to enhance the yield, increase solubility or aid
crystallization2
. These process solvents cannot be completely
removed by practical manufacturing practices such as freeze–drying
and drying at high temperature under vacuum. Therefore, some
residual solvents may remain in drug substance material4
. Typically,
the final purification step in many pharmaceutical drug-substance
processes involves a crystallization step, and the crystals thus
formed can entrap a finite amount of solvent from the mother liquor
that may cause degradation of the drug, OVIs may also contaminate
the products during packaging, storage in warehouses and/or during
transportation3
.
While solvents play a key role in the production of
pharmaceuticals, there is also a downside, as many of the
solvents used have toxic or environmentally hazardous properties.
Complete removal of residual levels of solvents is impractical from a
manufacturing standpoint, so it is inevitable that traces will remain inthe final product. The presence of these unwanted chemicals even
in small amounts may influence the efficacy, safety and stability of
the pharmaceutical products. Because residual solvents have no
therapeutic benefits but may be hazardous to human health and
the environment, it must be ensured that they are either not present
in products or are only present below recommended acceptable
levels. It is a drug manufacturer’s responsibility to ensure that any
OVIs present in the final product are not harmful to humans and
that medicinal products do not contain levels of residual solvents
higher than recommended safety limits. Solvents known to cause
unacceptable toxicity should be avoided unless their use can be
justified on the basis of a risk-benefit assessment2
. Because of their
proven or potential toxicity, the level of residual solvents is controlled
through national and international guidelines, for example, through
the FDA and International Conference on Harmonization.

“All drug substances, excipients, and products are subject to
relevant control of residual solvents, even when no test is specified
in the individual monograph.”
Regulatory and Compliance Environment
One of the essential aspects of pharmaceutical manufacturing
is regulatory compliance, which typically encompasses two aspects.
The first is compliance with private sets of standards based on
an applicant filing with a regulatory agency, which requires the
applicant to report the determined residual solvent levels in a
number of representative batches of pharmaceutical product to
establish typical levels of solvent contamination that can routinely
be achieved. Based on a statistical evaluation of the reported
data, a specification is agreed for solvents used in the final step of
the process and a decision made on whether testing is required
for solvent used at earlier stages in the process. To arrive at a
specification that is a measure of the routine performance of the
process, regulatory agencies require numerical data rather than
reporting compliance with a limit test.

Internationally, there has been a need to establish regulatory
standard guidelines. In 1997, The International Conference on
Harmonization of Technical Requirements for Registration of
Pharmaceuticals for Human Use (ICH), through its Q3C Expert
working group formed by regulators from the three ICH regions,
industry representatives and interested parties/observers, finalized
the Q3C guideline on residual solvents. Essentially, ICH has
consistently proposed that limits on organic solvents be set at levels
that can be justified by existing safety and toxicity data, and also kept
proposed limits within the level achievable by normal manufacturing
processes and within current analytic capabilities.
The second aspect is compliance with public standards set
by Pharmacopoeias from the three ICH regions (United States
Pharmacopoeia (USP), European Pharmacopoeia (Ph. Eur.) and
Japanese Pharmacopoeia (JP)) and also with local pharmacopoeias
from countries outside the ICH regions. In the recent past, guidelines
for organic residual solvents for public standards have generally
been vague and not up-to-date. The pharmacopoeial approach
was typically a limit test for residual solvents, employing standard
addition3
. The USP set the official limits in USP 23rd edition in the
general chapter 467, Organic Volatile Impurities5
. Very early on,
the Ph. Eur. employed the ICH Q3C regulatory approach and
updated the acceptance limits but kept the methodology as a limit
test based on standard addition. The general method in Ph. Eur. for
Identification and Control of Residual Solvents in drug substances
defines a general procedure and describes two complementary gas
chromatography (GC) conditions for identifying unknown solvents.
‘‘System A’’ is recommended for general use and is equivalent
to ‘‘Methods IV and V’’ of the USP for analysis of volatile organic
impurities ‘‘System B’’ is used to confirm identification and to solve
co-elutions. Implementation of this general method is a subject of
debate in the pharmaceutical industry due to its limited selectivity
and sensitivity3
. Historically, until its 27th edition, the USP restricted
its listing of residual solvents to those of Class 1 and neglected to

consider the wide range of organic solvents used routinely in the
pharmaceutical industry. Furthermore, the limits stated for Class 1
solvents like benzene, chloroform, 1, 4-dioxane, methylene chloride,
and 1, 1, 1-trichloroethane are in the range 2–600 (ppm) and are
therefore not in concordance with the ICH guideline. Residual
solvent testing using GC has been included in the pharmacopeias
for almost 20 years, while residual solvent-test methods have
been reported in the literature since before that. With USP 28, the
public standard for residual solvents was updated to comply with
the ICH Q3C guideline, but the methodology (the same limit-test
approach as Ph. Eur.) and the targeted monographs were not
considered appropriate by industry and regulators, leading to a
notice postponing implementation in USP 296
.
ICh Guideline
The objective of this guidance is to recommend acceptable
amounts for residual solvents in pharmaceuticals for the safety of
the patient. The guidance recommends use of less toxic solvents
and describes levels considered to be toxicologically acceptable
for some residual solvents.
Residual solvents in pharmaceuticals are defined here as
‘organic volatile chemicals that are used or produced in the
manufacture of drug substances or excipients, or in the preparation
of drug products’. This guidance does not address solvents
deliberately used as excipients nor does it address solvates.
However, the content of solvents in such products should be
evaluated and justified.
Since there is no therapeutic benefit from residual solvents,
all residual solvents should be removed to the extent possible to
meet product specifications, good manufacturing practices, or other
quality-based requirements. Drug products should contain no higher
levels of residual solvents than can be supported by safety data.
Some solvents that are known to cause unacceptable toxicities
(Class 1) should be avoided in the production of drug substances,
excipients, or drug products unless their use can be strongly justified
in a risk-benefit assessment. Some solvents associated with less
severe toxicity (Class 2) should be limited in order to protect patients
from potential adverse effects. Ideally, less toxic solvents (Class 3)
should be used where practical7

Scope of the Guidance
Residual solvents in drug substances, excipients, and drug
products are within the scope of this guidance. Therefore, testing
should be performed for residual solvents when production or
purification processes are known to result in the presence of such
solvents. It is only necessary to test for solvents that are used or
produced in the manufacture or purification of drug substances,
excipients, or drug products. Although manufacturers may choose
to test the drug product, a cumulative method may be used to
calculate the residual solvent levels in the drug product from the
levels in the ingredients used to produce the drug product. If the
calculation results in a level equal to or below that recommended
in this guidance, no testing of the drug product for residual solvents
need be considered. If, however, the calculated level is above the
recommended level, the drug product should be tested to ascertain
whether the formulation process has reduced the relevant solvent
level to within the acceptable amount. Drug product should also be
tested if a solvent is used during its manufacture.
This guidance does not apply to potential new drug substances,
excipients, or drug products used during the clinical research
stages of development, nor does it apply to existing marketed
drug products. The guidance applies to all dosage forms androutes of administration. Higher levels of residual solvents may be
acceptable in certain cases such as short-term (30 days or less)
or topical application. Justification for these levels should be made
on a case-by-case basis7
.
Classification of Residual Solvents
OVIs are classified into three classes on the basis of their
toxicity level and the degree to which they can be considered
an environmental hazard. The list provided in the guideline is
not exhaustive, and one should evaluate the synthesis and
manufacturing processes for all possible residual solvents.
The term, tolerable daily intake (TDI), is used by the International
Program on Chemical Safety (IPCS) to describe exposure limits
of toxic chemicals and the term, acceptable daily intake (ADI), is
used by the World Health Organization (WHO) and other national
and international health authorities and institutes. The new term,
permitted daily exposure (PDE), is defined in the present guidance
as a pharmaceutically acceptable intake of residual solvents to avoid
confusion of differing values for ADI’s of the same substance7
.
Residual solvents are classified on the basis
of risk assessment:
1. Class 1 solvents (Solvents to be avoided): Known human
carcinogens, strongly suspected human carcinogens, and
environmental hazards.
2. Class 2 solvents (Solvents to be limited): Non-genotoxic
animal carcinogens or possible causative agents of other
irreversible toxicity such as neurotoxicity or teratogenicity.3. Class 3 solvents (Solvents with low toxic potential): Solvents
with low toxic potential to man; no health-based exposure limit
is needed. Class 3 solvents have PDE’s of 50 milligrams (mg)
or more per day.
4. Class 4 solvents (Solvents for which no adequate
toxicological data was found): No adequate toxicological
data on which to base a PDE (permitted dose exposure) was
found.
Environmental Regulation of Organic Volatile
Solvents
Several of the residual solvents frequently used in the
production of pharmaceuticals are listed as toxic chemicals in
Environmental Health Criteria (EHC) monographs and in the
Integrated Risk Information System (IRIS). The objectives of such
groups as the International Programme on Chemical Safety (IPCS),
the U.S. Environmental Protection Agency (EPA), and the U.S.
Food and Drug Administration (FDA) include the determination
of acceptable exposure levels. The goal is protection of human
health and maintenance of environmental integrity against the
possible deleterious effects of chemicals resulting from long-term
environmental exposure. The methods involved in the estimation
of maximum safe exposure limits are usually based on long-term
studies. When long-term study data are unavailable, shorter term
study data can be used with modification of the approach such as
use of larger safety factors. The approach described therein relates
primarily to long-term or lifetime exposure of the general population
in the ambient environment (i.e., ambient air, food, drinking water,
and other media) 7
.
Limits of Residual Solvents
Solvents to Be Avoided: Solvents in Class 1 (Table 1) should
not be employed in the manufacture of drug substances, excipients,and drug products because of their unacceptable toxicity or their
deleterious environmental effect. However, if their use is unavoidable
in order to produce a drug product with a significant therapeutic
advance, then their levels should be restricted as shown in Table
1, unless otherwise justified. The solvent 1, 1, 1-Trichloroethane
is included in Table 1 because it is an environmental hazard. The
stated limit of 1,500 ppm is based on a review of the safety data

Analysis of Residual Solvent in
Pharmaceuticals
The analysis of residual solvents is an essential part in the
quality control of drug substances used in preclinical or clinical
trials as well as for use in commercial drug products. Residual
solvent analysis of bulk drug substance and finished pharmaceutical
products is necessary for a number of reasons such as –
1. High levels of residual organic solvents represent a risk to human
health because of their toxicity.
2. Residual organic solvents also play a role in the physicochemical
properties of the bulk drug substance. Crystalline nature of the
bulk drug substance can be affected. Differences in the crystal
structure of the bulk drug may lead to changes in dissolution
properties and problems with formulation of the finished
product.
3. Finally, residual organic solvents can create odor problems
and color changes in the finished product and, thus, can lead
to consumer complaints.
4. Often, the main purpose for residual solvent testing is in its use
as a monitoring check for further drying of bulk pharmaceuticals
or as a final check of a finished product.

5. Testing for solvent content in intermediates may need to be
performed if a critical amount of residual solvent(s) remaining
in the intermediate can alter the next step of the process.
6. Knowledge of the solvent content in the starting materials may
help to the development chemist to understand the synthetic
routes and predict potential process related impurities.
7. Knowing the solvents used in the process allows the development
chemist to look for possible compound- solvent interactions
which can lead to the formation of impurities5, 16
.
Residual solvent analysis can be performed with a large array of
analytical techniques17. The most popular, and the most appropriate,
specific solvent analysis is testing by gas chromatography (GC).
Modern capillary-column gas chromatographs can separate a large
number of volatile components, permitting identification through
retention characteristics and detection at ppm levels using a broad
range of detectors5
.Gas chromatographic testing can be categorized
into three main procedures according to the means of introducing
the sample into the instrument. A direct gas chromatographic
procedure is one in which a portion of the actual drug substance
or formulation is injected into a GC system. The drug substance
is usually dissolved in an appropriate solvent and loaded into a
syringe and injected. Headspace analysis, on the other hand, is
an indirect testing procedure. The analysis is conducted when a
volume of gas above the drug substance or formulation is collected
and analyzed by a gas chromatograph. Finally, solid-phase microextraction (SPME) is making much progress in recent years for
residual solvent testing. In SPME, a silica fiber coated with a sorbent
is used to collect and concentrate the volatile solvents. The volatiles
are then thermally desorbed in the inlet of the gas chromatograph
and analyzed18
.
Many alternatives to gas chromatography have been used to
determine the level of residual solvent in pharmaceutical products.
Many of these procedures are either nonspecific—that is, the
solvents are not identified—or they have high detection limits, so
they are inappropriate for the detailed product characterization
required for a regulatory submission. The oldest and simplest
method for determining the quantity of volatile residue is measuring

the weight loss of a sample during heating. LOD method is widely
used, particularly for Class 3 solvents, due to its simplicity and
ease of introduction into even the most basic analytical laboratory5
.
Another approach is to use thermogravimetric analysis (TGA),
which is a well-known method for the quantitative analysis of the
loss of volatile components from a sample18. Spectroscopic and
spectrometric methods have generally lacked the low detection
limits needed for toxic residual solvents, although the detection limits
would be applicable for ICH class 2 and 3 solvents. In the case of
Infrared Spectroscopy (IR), a detection limit above 100 ppm and
lack of accuracy at low concentrations of residual solvent has been
reported. For NMR also high detection limit has been reported5
.
CONCLUSION
Whenever organic solvents are used in the production of
pharmaceutical products, especially in the last processing steps,
the content of residual solvent in the final product should be
analyzed. The complete removal of residual level of these solvents
is impracticable and traces always remain in the final products.
The presence of these residual solvents even in small amounts
has a negative influence not only on the quality of products but
also on human health. Acceptability of residual solvents seems to
be best judged following the ICH residual solvent guideline which
is adopted by the USP, EP and JP; it classifies the solvent into
four groups. In class 1 are included the most toxic solvents which,
unless strongly justified, should be avoided. For the toxic solvents
of class 2, the limits are expressed as concentrations (ppm) and
additionally in the case of known daily drug intake, by the very
important ‘permitted daily exposure’ (PDE). The class 3 includes
the solvents with low toxic potential for which the general limit is
set at 0.5%. The class 4 includes solvents for which no adequate
toxicological data was found.

How much does quality cost? Most companies would be hard-pressed to translate “quality” into dollars and cents. What they realize, however, is that a lack of quality could cost millions of dollars in rework, scrap, recall, or even liability lawsuits.

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DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK PHARMACEUTICALS LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 29 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international,
etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules
and implementation them on commercial scale over a 29 year tenure till date Aug 2016, Around 30 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 25 Lakh plus views on dozen plus blogs, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 13 lakh plus views on New Drug Approvals Blog in 212 countries......http://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

All about Drugs, live, by DR ANTHONY MELVIN CRASTO, Worlddrugtracker, Helping millions, 9 million hits on google, pushing boundaries,2.5 lakh plus connections worldwide, 17 lakh plus VIEWS on this blog in 214 countries, The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent, USE CTRL AND+ KEY TO ENLARGE BLOG VIEW........................A 90 % paralysed man in action for you, I am suffering from transverse mylitis and bound to a wheel chair, With death on the horizon, nothing will not stop me helping you, except God

A site by Dr Anthony Melvin Crasto, worlddrugtracker for helping organic chemists with websites, trying to get information at one place, easy picks for users. million hits on google, purely academic, non commercial and free from advertisements, pushing boundaries, world acclamation for efforts, email amcrasto@gmail.com, +91 9323115463, India